Binding Affinity and Capacity for the Uremic Toxin Indoxyl Sulfate

Abstract

Protein binding prevents uremic toxins from removal by conventional extracorporeal therapies leading to accumulation in maintenance dialysis patients. Weakening of the protein binding may enhance the dialytic elimination of these toxins. In ultrafiltration and equilibrium dialysis experiments, different measures to modify the plasma binding affinity and capacity were tested: (i), increasing the sodium chloride (NaCl) concentration to achieve a higher ionic strength; (ii), increasing the temperature; and (iii), dilution. The effects on the dissociation constant KD and the protein bound fraction of the prototypical uremic toxin indoxyl sulfate (IS) in plasma of healthy and uremic individuals were studied. Binding of IS corresponded to one site binding in normal plasma. KD increased linearly with the NaCl concentration between 0.15 (KD = 13.2 ± 3.7 µM) and 0.75 M (KD = 56.2 ± 2.0 µM). Plasma dilution further reduced the protein bound toxin fraction by lowering the protein binding capacity of the plasma. Higher temperatures also decreased the protein bound fraction of IS in human plasma. Increasing the NaCl concentration was effective to weaken the binding of IS also in uremic plasma: the protein bound fraction decreased from 89% ± 3% to 81% ± 3% at 0.15 and 0.75 M NaCl, respectively. Dilution and increasing the ionic strength and temperature enhance the free fraction of IS allowing better removal of the substance during dialysis. Applied during clinical dialysis, this may have beneficial effects on the long-term outcome of maintenance dialysis patients.

A possible link between polyunsaturated fatty acids and uremic toxins from the gut microbiota in hemodialysis patients: A hypothesis

“…Consequently, uremic toxins have been identified as a relevant cause of cardiovascular mortality in CKD patients . Under physiologic conditions, these compounds are eliminated by the kidney through the urine . Nevertheless, CKD patients have a compromised renal clearance; therefore, these solutes tend to accumulate in the organs.…”

“…Sudlow et al proposed that HSA has two specific drug binding sites, site I and site II, which are assigned to subdomains IIA and IIIA, respectively . Most of the circulating uremic toxins are found to interact with both binding sites Sudlow I and II, which are located in the subdomains IIA and IIIA, via electrostatic and/or van der Waals forces (binding affinity) . However, fatty acids seem to be the main endogenous ligand of HSA (approximately 0.1–2.0 moles of fatty acids per mole of protein), and multiple binding sites are used for monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) .…”

Indoxyl sulphate and kidney disease: Causes, consequences and interventions

“…Two protein metabolites in particular, indoxyl sulphate (IS; a tryptophan derivative) and p ‐cresyl sulphate (a derivative of tyrosine and phenylalanine), have become readily studied due to their inability to be removed by dialysis, and their associations with CKD progression and cardiovascular disease . Both toxins competitively bind to Sudlow's site II (subdomain IIIA) on the albumin molecule through electrostatic and Van der Waals forces . The scope of the present review is to characterize the causes, consequences and potential therapeutic manipulation of serum IS accumulation in patients with CKD.…”

Role of Gut-Derived Protein-Bound Uremic Toxins in Cardiorenal Syndrome and Potential Treatment Modalities

“…The potential approach for this propose, including increasing ionic strength using sodium chloride, increasing temperature from room to body temperature and dilution, has been demonstrated to decrease the protein-bound fraction and increase the free fraction of IS, thereby likely contributing to better removal during dialysis. 23,127 Kidney Transplantation Successful kidney transplantation has shown benefits on survival, 128 preventing progression of CKD, recovery of cardiac function 129 and regression of cardiac fibrosis. 15 Study demonstrating such outcomes in relation to reduced levels of problematic non-dialyzable PBUTs is extremely rare in post-kidney transplantation patients.…”